Bayesian structural time series, an alternative to interrupted time series in the right circumstances.
Compare two approaches to analyzing time series data-interrupted time series with segmented regression (ITS-SR) and Bayesian structural time series using the CausalImpact R package (BSTS-CI)-highlighting advantages, disadvantages, and implementation considerations. We analyzed electronic health records using each approach to estimate the antibiotic prescribing reduction associated with an educational program delivered to Australian primary care physicians between 2012 and 2017. Two outcomes were considered: antibiotics for upper respiratory tract infections (URTIs) and antibiotics of specified formulations. For URTI indication prescribing, average monthly prescriptions changes were estimated at -4,550; (95% confidence interval, -5,486 to -3,614) and -4,270; (95% credible interval, -5,934 to -2,626) for ITS-SR and BSTS-CI, respectively. Similarly for specified formulation prescribing, monthly average changes were estimated at -7,923; (95% confidence interval, -15,887 to 40) for ITS-SR and -20,269; (95% credible interval, -25,011 to -15,635) for BSTS-CI. Differing results between ITS-SR and BSTS-CI appear driven by divergent explanatory and outcome series trends. The BSTS-CI may be a suitable alternative to ITS-SR only if the explanatory series represent the secular trend of the outcome series before the intervention and are equally affected by exogenous or confounding factors. When appropriately applied, BSTS-CI provides an alternative to ITS with more readily interpretable Bayesian effect estimates.


The changing pattern of prenatal care utilization in the United States, 1981-1995, using different prenatal care indices.
Two measures traditionally used to examine adequacy of prenatal care indicate that prenatal care utilization remained unchanged through the 1980s and only began to rise slightly in the 1990s. In recent years, new measures have been developed that include a category for women who receive more than the recommended amount of care (intensive utilization). To compare the older and newer indices in the monitoring of prenatal care trends in the United States from 1981 to 1995, for the overall population and for selected subpopulations. Second, to examine factors associated with receiving intensive utilization. Cross-sectional and trend analysis of national birth records. The United States. All live births between 1981 and 1995 (N=54 million). Trends in prenatal care utilization, according to 4 indices (the older indices: the Institute of Medicine Index and the trimester that care began, and the newer indices: the R-GINDEX and the Adequacy of Prenatal Care Utilization Index). Multiple logistic regression was used to assess the risk of intensive prenatal care use in 1981 and 1995. The newer indices showed a steadily increasing trend toward more prenatal care use throughout the study period (R-GINDEX, intensive or adequate use, 32.7% in 1981 to 47.1 % in 1995; the Adequacy of Prenatal Care Utilization Index, intensive use, 18.4% in 1981 to 28.8% in 1995), especially for intensive utilization. Women having a multiple birth were much more likely to have had intensive utilization in 1995 compared with 1981 (R-GINDEX, 22.8% vs 8.5%). Teenagers were more likely to begin care later than adults, but similar proportions of teens and adults had intensive utilization. Intensive use among low-risk women also increased steadily each year. Factors associated with a greater likelihood of receiving intensive use in 1981 and 1995 were having a multiple birth, primiparity, being married, and maternal age of 35 years or older. The proportion of women who began care early and received at least the recommended number of visits increased between 1981 and 1995. This change was undetected by more traditional prenatal care indices. These increases have cost and practice implications and suggest a paradox since previous studies have shown that rates of preterm delivery and low birth weight did not improve during this time.


Structure of Importin13-Ubc9 complex: nuclear import and release of a key regulator of sumoylation.
Importin13 (Imp13) is an unusual β-karyopherin that is able to both import and export cargoes in and out of the nucleus. In the cytoplasm, Imp13 associates with different cargoes such as Mago-Y14 and Ubc9, and facilitates their import into the nucleus where RanGTP binding promotes the release of the cargo. In this study, we present the 2.8 Å resolution crystal structure of Imp13 in complex with the SUMO E2-conjugating enzyme, Ubc9. The structure shows an uncommon mode of cargo-karyopherin recognition with Ubc9 binding at the N-terminal portion of Imp13, occupying the entire RanGTP-binding site. Comparison of the Imp13-Ubc9 complex with Imp13-Mago-Y14 shows the remarkable plasticity of Imp13, whose conformation changes from a closed ring to an open superhelix when bound to the two different cargoes. The structure also shows that the binding mode is compatible with the sumoylated states of Ubc9. Indeed, we find that Imp13 is able to bind sumoylated Ubc9 in vitro and suppresses autosumoylation activity in the complex.


Protective role of sertraline against 3-nitropropionic acid-induced cognitive dysfunction and redox ratio in striatum, cortex and hippocampus of rat brain.
Huntington's disease (HD) is an inherited progressive neurodegenerative disorder in human characterized by progressive loss of movement and cognitive disturbances. 3-nitropropionic acid (3-NP; a mitochondrial toxin) produces age-dependent oxidative linked striatal damage, responsible for HD like symptoms. In the present study protective effect of sertraline in 3-NP induced HD like symptoms was evaluated in rats. Systemic administration of 3-NP (10 mg/kg for 14 days) resulted in impairment of memory as assessed in Morris water maze and elevated plus paradigm tasks. Biochemical analysis revealed that systemic 3-NP administration significantly impaired reduced glutathione, total glutathione, oxidized glutathione and glutathione-S-transferase levels, whereas the level of acetylcholinesterase enzyme increased in striatum, cortex and hippocampus regions of rat brain. Sertraline (5 and 10 mg/kg po) treatment once daily for 14 days significantly improved cognitive performance tasks and glutathione levels in 3-NP treated group. However, combination of yohimbine (2 mg/kg) (non selective serotonin receptors antagonist) with the higher dose of sertraline (10 mg/kg) did not influence the protective action of sertraline. Result shows that neuroprotective and antioxidant like effect of sertraline is independent of its conventional action on 5-HT receptor.


Probing the role of axial methionine in the blue copper center of azurin with unnatural amino acids.
Expressed protein ligation was used to replace the axial methionine of the blue copper protein azurin from Pseudomonas aeruginosa with unnatural amino acids. The highly conserved methionine121 residue was replaced with the isostructural amino acids norleucine (Nle) and selenomethionine (SeM). The UV-visible absorption, X- and Q-band EPR, and Cu EXAFS spectra of the variants are slightly perturbed from WT. All variants have a predominant S(Cys) to Cu(II) charge transfer band around 625 nm and narrow EPR hyperfine splittings. The Se EXAFS of the M121SeM variant is also reported. In contrast to the small spectral changes, the reduction potentials of M121SeM, M121Leu, and M121Nle are 25, 135, and 140 mV, respectively, higher than that of WT azurin. The use of unnatural amino acids allowed deconvolution of different factors affecting the reduction potentials of the blue copper center. A careful analysis of the WT azurin and its variants obtained in this work showed the large reduction potential variation was linearly correlated with the hydrophobicity of the axial ligand side chains. Therefore, hydrophobicity is the dominant factor in tuning the reduction potentials of blue copper centers by axial ligands.


The complement-activating capacity of maternal IgG antibodies to blood group A in paired mother/child serum samples.
The aim of this study was to investigate whether IgG antibodies to blood group A bind or activate complement after crossing the placenta. IgG anti-A concentrations as well as C1-q-binding and the capacity of anti-A to form the C5b-9 membrane attack complex were measured in sera of 61 mother/child pairs. The enzyme-linked immunosorbent assay was used to quantitate anti-A or anti-B in maternal and neonatal serum samples. The concentrations of IgG anti-A in ABO-identical and ABO-compatible children born to type O or B mothers correlated significantly with maternal concentrations (p < 0.05), whereas type A or AB children had strikingly diminished concentrations of IgG anti-A. The IgG anti-A concentrations were analyzed in two different groups: first, 44 mother/child pairs with mothers and children group O or B (group I), and second, 17 pairs with mothers group O or B and children group A or AB (group II). In group I, identical or compatible pairs with regard to IgG anti-A, a significant correlation was found by Spearman's rank analysis, whereas the same analysis revealed no significant correlation in group II. The capacity of anti-A to activate complement was also more marked in newborns who were ABO-identical or ABO-compatible with their mothers, and this capacity was virtually absent in cord blood samples from incompatible babies. Tests for complement-dependent or complement-independent ABO blood group antibodies must be interpreted in the light of the blood group of the child.


Ginsenoside Re prevents angiotensin II-induced gap-junction remodeling by activation of PPARγ in isolated beating rat atria.
Ginsenoside Re (G-Re), a major ginsenoside in ginseng, has many beneficial pharmacological effects on negative cardiac contractility, electromechanical alternans, antiarrhythmia, angiogenic regeneration and cardiac electrophysiological function. However, effects of G-Re on gap-junction remodeling are unclear. Therefore, this study aimed to investigate the effect of G-Re on angiotensin II (Ang II)-induced downregulation of connexin-40 (CX40) and -43 (CX43) in beating rat left atria. In this study, the isolated perfused beating rat atrial model was used and atrial gap-junction remodeling was induced by Ang II. In vivo hemodynamic experiments were analyzed with a biological recorder. Changes in protein expression were analyzed by western blot. G-Re attenuated Ang II-induced abnormal changes in heart rate, MAP, LVESP, LVEDP, +dp/dt max, -dp/dt min, P wave amplitude, P-R interval and P wave length. This indicated a dose-dependent preventive role against Ang II-induced hyper hemodynamics in rats. Atrial activities of p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-B (NF-κB) and activator protein 1 (AP-1) were significantly increased by Ang II, as was expression of atrial collagen I and matrix metalloproteinase 2 (MMP2). Atrial CX40 and CX43 expression was downregulated by Ang II. These Ang II-induced atrial effects were blocked by G-Re, as well as rosiglitazone, an agonist of peroxisome proliferator-activated receptor γ (PPARγ), in a dose-dependent manner. However, this inhibition was abolished by the PPARγ inhibitor GW9662. G-Re may suppress Ang II-induced downregulation of CX40 and CX43, by activating PPARγ signaling, in isolated perfused beating rat atria.


Lateral visual pathway of giant barnacle.
1. We have studied the responses to light, conduction down the axons, and anatomical projections of the photoreceptors of the lateral eye in the giant barnacle, Balanus nubilus. By recording intracellularly from ganglion cells that respond to visual input, we have described convergence of the lateral and median visual pathways. 2. Each lateral eye contains three photoreceptor cells, two large and one small. Cobalt filling of single large lateral receptor axons demonstrated that they end in a restricted ovoid bush on the ipsilateral side of the ganglion in approximately the same region in which the median receptors arborize. 3. The lateral receptors have dark resting potentials and responses to light similar to those previously described for the receptors of the median eye. Like the median receptors, the lateral receptors conduct visual signals decrementally, although their axons may be twice as long (14-25 mm). 4. Passing current of either polarity into either of the large receptors produced no detectable voltage change in the other cell. Action potentials elicited in either cell by stimulating it in the presence of tetraethylammonium ion were not detected in the other cell. Light-induced membrane noise in one cell did not correlate with noise in the other. Thus, like the receptors of the median eye, the large receptors of the lateral eye are not electrically coupled. 5. By shadowing each ocellus individually, we have shown that the signals from the median and lateral photoreceptors converge at the level of the second-order cells described for the median pathway. Shadowing the median or a lateral eye gave rise to synergistic responses in second-, third-, and all higher order ganglion cells studied. No cells were found that were driven solely by the lateral eyes. Thus, the lateral and median visual pathways are highly convergent.


Inhibition of ErbB kinase signalling promotes resolution of neutrophilic inflammation.
Neutrophilic inflammation with prolonged neutrophil survival is common to many inflammatory conditions, including chronic obstructive pulmonary disease (COPD). There are few specific therapies that reverse neutrophilic inflammation, but uncovering mechanisms regulating neutrophil survival is likely to identify novel therapeutic targets. Screening of 367 kinase inhibitors in human neutrophils and a zebrafish tail fin injury model identified ErbBs as common targets of compounds that accelerated inflammation resolution. The ErbB inhibitors gefitinib, CP-724714, erbstatin and tyrphostin AG825 significantly accelerated apoptosis of human neutrophils, including neutrophils from people with COPD. Neutrophil apoptosis was also increased in Tyrphostin AG825 treated-zebrafish in vivo. Tyrphostin AG825 decreased peritoneal inflammation in zymosan-treated mice, and increased lung neutrophil apoptosis and macrophage efferocytosis in a murine acute lung injury model. Tyrphostin AG825 and knockdown of egfra and erbb2 by CRISPR/Cas9 reduced inflammation in zebrafish. Our work shows that inhibitors of ErbB kinases have therapeutic potential in neutrophilic inflammatory disease.


Norovirus prevalence and estimated viral load in symptomatic and asymptomatic children from rural communities of Vhembe district, South Africa.
Human Norovirus (NoV) is recognized as a major etiological agent of sporadic acute gastroenteritis worldwide. This study describes the clinical features associated with Human NoV occurrence in children and determines the prevalence and estimated viral burden of NoV in symptomatic and asymptomatic children in rural South Africa. Between July 2014 and April 2015, outpatient children under 5 years of age from rural communities of Vhembe district, South Africa, were enrolled for the study. A total of 303 stool specimens were collected from those with diarrhea (n=253) and without (n=50) diarrhea. NoVs were identified using real-time one-step RT-PCR. One hundred and four (41.1%) NoVs were detected (62[59.6%] GII, 16[15.4%] GI, and 26[25%] mixed GI/GII) in cases and 18 (36%) including 9(50%) GII, 2(11.1%) GI and 7(38.9%) mixed GI/GII in controls. NoV detection rates in symptomatic and asymptomatic children (OR=1.24; 95% CI 0.66⿿2.33) were not significantly different. Comparison of the median CT values for NoV in symptomatic and asymptomatic children revealed significant statistical difference of estimated GII viral load from both groups, with a much higher viral burden in symptomatic children. Though not proven predictive of diarrhea disease in this study, the high detection rate of NoV reflects the substantial exposure of children from rural communities to enteric pathogens possibly due to poor sanitation and hygiene practices. The results suggest that the difference between asymptomatic and symptomatic children with NoV may be at the level of the viral load of NoV genogroups involved.


A typical presentation of dengue fever in a G6PD deficient patient: A case report.
Dengue is a mosquito-borne viral disease that has rapidly spread in the recent years, particularly in South Asia. While haematologic complications, such as cytopenia and bleeding, may occur in severe dengue infection, reports of haemolytic anaemia in dengue fever are scant. We report a patient who developed haemolytic anaemia following dengue fever. A 45 years old gentleman presented with five-day history of fever and was recently diagnosed with dengue fever. He developed jaundice and started vomiting on the third day of his clinical course. His laboratory investigations revealed deranged liver profile, Coombs negative haemolytic anaemia and G6PD deficiency. He was treated conservatively with fluids and blood transfusions. His liver functions and haemolytic anaemia gradually resolved. This case highlights the importance of recognising dengue fever-induced haemolytic anaemia in a G6PD deficient patient by physicians and pathologists, enabling better diagnosis and improved management of this life-threatening condition.


Tracking the interaction of drug molecules with individual mesoporous amorphous calcium phosphate/ATP nanocomposites - an X-ray spectromicroscopy study.
Adenosine triphosphate (ATP) biomolecules play critial roles in the biomineralization process during the formation of amorphous calcium phosphate composites (ACPC), and ACPC is an important drug carrier due to its significant advantages of biocompatibility and biodegradability. Hence, studying the behavior of ACPC nanodrug carriers is crucial to investigate the structural regulation of biomimetic minerals and calcium phosphate (CaP)-based drug delivery systems. However, it is difficult to probe these interactions using traditional characterization methods. In this paper, XANES analysis together with STXM successfully provided a method to reveal the interaction of ATP and drug molecules with individual mesoporous ACPC. We found that the adenosine and phosphate groups of ATP biomolecules coordinated with Ca2+ and played critical roles in the formation of ACPC; drug molecules with the -COOH groups were linked to Ca2+via carboxylic acid groups primarily by electrostatic interactions, and the N-containing ring structures within the drug molecules also coordinated with Ca2+.


Four-dimensional computed tomography-based biomechanical measurements of pulmonary function and their correlation with clinical outcome for lung stereotactic body radiation therapy patients.
Functional image guided radiotherapy allows for the delivery of an equivalent dose to tumor targets while sparing high ventilation lung tissues. In this study, we investigate whether radiation dose to functional lung is associated with clinical outcome for stereotactic body radiation therapy (SBRT) patients. Four-dimensional computed tomography (4DCT) images were used to assess lung function. Deformable image registration (DIR) was performed from the end-inhale phase to the end-exhale phase with resultant displacement vectors used to calculate ventilation maps. In addition to the Jacobian-based ventilation we introduce a volumetric variation method (Rv) based on a biomechanical finite element method (FEM), to assess lung ventilation. Thirty NSCLC patients, treated with SBRT, were evaluated in this study. 4DCT images were used to calculate both Jacobian and Rv-based ventilation images. Areas under the receiver operating characteristic curve (AUC) were used to assess the predictive power of functional metrics. Metrics were calculated over the whole lung as well as high and low ventilated regions. Ventilation in dose regions between 1 and 5 Gy had higher AUC values compared to other dose regions. Rv based ventilation imaging method also showed to be less spatially variant and less heterogeneous, and the resultant Rv metrics had higher AUC values for predicting grade 2+ dyspnea. Low dose delivered to high ventilation areas may also increase the risk of compromised pulmonary function. Rv based ventilation images could be useful for the prediction of clinical toxicity for lung SBRT patients.


Mental and manual rotation.
The relation between mental and manual rotation was investigated in 2 experiments. Experiment 1 compared the response times (RTs) of mental rotation about 4 axes in space with the RTs shown in the same task when participants were allowed to reorient the stimuli by means of rotational hand movements. For the 3 Cartesian axes, RT functions were quantitatively indistinguishable. Experiment 2 investigated interference between mental rotation and 4 kinds of simultaneously executed hand movements that did not reorient the stimuli. Interference was observed only when axes of manual and mental rotation coincided in space. Regardless of the hand used, concordant rotational directions facilitated, whereas discordant directions inhibited, mental rotation. The results suggest that mental object rotation and rotatory object manipulation share a common process that is thought to control he dynamics of both imagined and actually performed object reorientation.


[Effect of radiation and radioprotectors on the properties of hematopoietic stem cells].
Sublethal irradiation of donors leads to a change in some properties of bone marrow haemopoietic stem cells (HSC) during the exponential growth (days 1-8) of the syngeneic recipients in the spleen. They are: an increase in the rate of proliferation, a slight reduction in time of the population doubling, and a tendency toward an increase in the percentage of cells settled in the spleen after transplantation. These changes in the properties of HSC provide a more rapid repopulation thereof as compared to HSC of intact mice. In all appearance, a pretreatment of donors with AET and 2ADT does not influence the HSC changes induced by radiation, and, at the same time, retains the number of HSC at a high level.


"Work with us… to make it more accessible". What women with intellectual disabilities want from infant-feeding health resources: an exploratory study.
More women with intellectual disabilities are becoming mothers but fewer are known to breastfeed compared with other women. Women with intellectual disabilities are entitled to accessible antenatal and infant feeding information, yet are rarely asked for their views on available resources. This article reports on the final stage of a UK project exploring how women with intellectual disabilities are supported to make infant feeding decisions. The wider project includes a scoping review and interviews with healthcare professionals, here we focus on the voices of the women themselves. Four women with an intellectual disability participated in a focus group where they were asked to give their views on the accessibility of currently available infant feeding resources and on alternative representations of infant feeding. All were interested in women's health issues, including infant feeding. Photo-elicitation was used to gather views on videos, bespoke 'Easy Read' material and several alternative representations of infant feeding. A transcription of the discussion was thematically analysed whilst a critical visual analysis was undertaken of the women's preferred images/resources. The study took place in Bristol, UK, during 2022. Two themes were identified from the group discussion: 'The desire for choice' and 'How easy is 'Easy Read'?' The desire for choice was expressed in terms through agreements and disagreements about preferred imagery, differing tastes, and reasons for these preferences. We identified a challenge to 'Easy Read' as a default standard and concerns that some forms of 'Easy Read' can confuse rather than inform. Critical visual analysis identified the importance of the story and social setting of the preferred infant feeding image. Findings suggest a need for a suite of resources, avoiding the one-size-fits-all approach, including people with an intellectual disability at every stage of the design and production process. Resources should recognise and embrace differences in terms of understanding, visual literacy and cultural taste, as well as being freely available to support women with intellectual disabilities to make informed infant feeding decisions. An accessible film was co-produced, to disseminate the findings from all three stages of the completed project.


Complement C3a and C5a modulate osteoclast formation and inflammatory response of osteoblasts in synergism with IL-1β.
There is a tight interaction of the bone and the immune system. However, little is known about the relevance of the complement system, an important part of innate immunity and a crucial trigger for inflammation. The aim of this study was, therefore, to investigate the presence and function of complement in bone cells including osteoblasts, mesenchymal stem cells (MSC), and osteoclasts. qRT-PCR and immunostaining revealed that the central complement receptors C3aR and C5aR, complement C3 and C5, and membrane-bound regulatory proteins CD46, CD55, and CD59 were expressed in human MSC, osteoblasts, and osteoclasts. Furthermore, osteoblasts and particularly osteoclasts were able to activate complement by cleaving C5 to its active form C5a as measured by ELISA. Both C3a and C5a alone were unable to trigger the release of inflammatory cytokines interleukin (IL)-6 and IL-8 from osteoblasts. However, co-stimulation with the pro-inflammatory cytokine IL-1β significantly induced IL-6 and IL-8 expression as well as the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) indicating that complement may modulate the inflammatory response of osteoblastic cells in a pro-inflammatory environment as well as osteoblast-osteoclast interaction. While C3a and C5a did not affect osteogenic differentiation, osteoclastogenesis was significantly induced even in the absence of RANKL and macrophage-colony stimulating factor (M-CSF) suggesting that complement could directly regulate osteoclast formation. It can therefore be proposed that complement may enhance the inflammatory response of osteoblasts and increase osteoclast formation, particularly in a pro-inflammatory environment, for example, during bone healing or in inflammatory bone disorders.


[3H]ouabain binding during the monolayer organization and cell cycle in MDCK cells.
The specific binding of [3H]ouabain in an epithelial cell line derived from a dog kidney (MDCK) was determined during epithelial reorganization and also during the cell cycle. In suspended cells, the specific binding of [3H]ouabain is reduced 67% compared with the binding obtained in a complete monolayer. After plating back these cells on a permeable support, both transepithelial electrical resistance and [3H]ouabain binding increase with time of incubation. [3H]ouabain binding decreases during S and G2 phases of the cell cycle to reach a minimum during mitosis and increases again during GI. The transepithelial electrical resistance, determined simultaneously, shows the same behavior. The reduction in the number of [3H]ouabain binding sites in two different circumstances in which the epithelial membrane organization is disrupted and the increase in [3H]ouabain binding sites when the epithelial membrane is reorganized are consistent with the hypothesis that the number of pumping sites responsible for the active step in the transepithelial active transport is additional to the number required to maintain the intracellular ionic composition.


Variants in the CRP gene as a measure of lifelong differences in average C-reactive protein levels: the Cardiovascular Risk in Young Finns Study, 1980-2001.
Genetic association studies have used variants in the C-reactive protein (CRP) gene to estimate causal effects of lifelong circulating CRP levels on disease endpoints. However, the extent to which the genetic variants are actually associated with lifelong circulating CRP levels has not been demonstrated empirically. In a population-based prospective cohort study (1980-2001) of 1,609 young Finns (768 men and 841 women), the authors genotyped five single nucleotide polymorphisms in the CRP gene (-717A/G, -286C/T/A, +1059G/C, +1444T/C, and +1846G/A) and assessed circulating CRP levels at ages 3-18 years and 24-39 years. The haplotypes from the five single nucleotide polymorphisms were associated with circulating CRP levels in childhood and adulthood, with the strongest effect being found for average CRP level across these two measures taken at two time points in the life course. In combination, the haplotype pairs accounted for 3.9%, 3.3%, and 5.0% of the variation in circulating CRP levels in childhood, in adulthood, and for the mean of CRP levels at both time points, respectively. These findings support the assumption that the above genetic variants define groups with long-term differences in circulating CRP levels.


Endovascular reversal of renovascular hypertension blunts cardiac dysfunction and deformation in swine.
Renovascular hypertension (RVH) induces hemodynamic and humoral aberrations that may impair cardiac function, structure and mechanics, including cardiac twist and deformation. Revascularization of a stenotic renal artery can decrease blood pressure (BP), but its ability to restore cardiac mechanics in RVH remains unclear. We hypothesized that percutaneous transluminal renal angioplasty (PTRA) would improve cardiac function and left ventricular (LV) deformation in swine RVH. Seventeen domestic pigs were studied for 16 weeks: RVH, RVH + PTRA and normal controls (n = 5-6 each). Global LV function was estimated by multidetector computed-tomography, and LV deformation by electrocardiographically triggered MRI tagging at the apical, mid, and basal LV levels. Cardiomyocyte hypertrophy, myocardial capillary density, and fibrosis were evaluated ex vivo. BP and wall thickness were elevated in RVH and decreased by PTRA, yet remained higher than in controls. LV myocardial muscle mass increased in RVH pigs, which also developed diastolic dysfunction, whereas cardiac output increased. Furthermore, both apical rotation and peak torsion angle increased in RVH compared with controls. Ex vivo, RVH induced myocardial fibrosis and vascular rarefaction. PTRA restored cardiac function and alleviated hypertrophy, vascular rarefaction, and fibrosis. PTRA also normalized apical rotation and peak torsion angle, and elevated basal peak radial strain and apical peak radial strain compared with RVH. In addition to cardiac LV adaptive hypertrophy and diastolic dysfunction, short-term RVH causes cardiac deformation. Despite only partial improvement in BP, PTRA effectively restored cardiac function and reversed abnormal mechanics. Hence, renal revascularization may be a useful strategy to preserve cardiac function in RVH.


Monitoring and assessment of dietary exposure to chemical contaminants.
The results of the Global Environment Monitoring System/Food Contamination Monitoring and Assessment Programme (GEMS/Food) and other monitoring programmes for priority contaminants in the diet, including lead, cadmium, mercury, polychlorinated biphenyls, organochlorine and organophosphorus pesticide residues and aflatoxin, are presented. These results are assessed with respect to established acceptable or tolerable intakes for these contaminants. While the assessments generally confirm the effectiveness of government efforts to prevent or reduce food contamination in industrialized countries, better exposure estimates for infants and children and other vulnerable groups should be calculated. In developing countries, little reliable information is available on the occurrence of food contamination. Without such information, the health of hundreds of millions of people may be threatened. For these countries, and especially those that employ older agricultural and industrial technologies, basic food contamination monitoring and assessment programmes should be established for at least those contaminants of priority concern. These programmes form an essential basis for developing effective intervention strategies and for efficient management of health and environment resources. In all countries, accidental and sporadic contamination is an ever present danger and continual vigilance is necessary to protect public health. All countries should identify institutions with the analytical capability to support epidemiological investigations of outbreaks of disease that may be associated with consumption of chemically contaminated food. All countries should participate in GEMS/Food to promote health-oriented, population-based monitoring at the national level.


Improving evoked response audiometry. Results of normative studies for machine scoring.
Normative studies were carried out with 8 adult subjects whose averaged evoked responses to auditory stimuli were scored visually and by a number of differently defined quantitative methods (machine scoring). In order to compare different scoring methods a common signal-to-noise ratio measure was introduced based on a model where noise is distributed normally and signal is additive. Visual and machine scoring proved to be approximately equally sensitive, but the latter lends itself to a superior testing procedure which takes only one-third as long for equivalent results and is not contaminated by subjective error. The authors believe that the greatest promise for improving evoked response audiometry lies in the exploration of the new techniques proposed earlier. Progress in proving out one of these techniques, fast periodic stimulation, is reported.


Crystallization and preliminary X-ray diffraction experiments of arylmalonate decarboxylase from Alcaligenes bronchisepticus.
Arylmalonate decarboxylase catalyses the enantioselective decarboxylation of alpha-aryl-alpha-methylmalonates to produce optically pure alpha-arylpropionates. The enzyme was crystallized with ammonium sulfate under alkaline pH conditions with the aim of understanding the mechanism of the enantioselective reaction. X-ray diffraction data collected to a resolution of 3.0 A at cryogenic temperature showed that the crystals belonged to the orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 83.13, b = 99.62, c = 139.64 A. This suggested that the asymmetric unit would contain between four and six molecules. Small-angle X-ray scattering revealed that the enzyme exists as a monomer in solution. Thus, the assembly of molecules in the asymmetric unit was likely to have been induced during the crystallization process.


[Straw return to rice paddy: soil carbon sequestration and increased methane emission].
Based on the long-term datasets of soil organic matter content and the observation data of rice paddies' methane (CH4) emission collected from the agricultural experiment stations across the country, the rice paddies in China were divided into single cropping and double cropping regions. The soil carbon sequestration potential of straw return in three types of rice paddies in the two regions, i. e., single cropping rice paddies, upland/paddy alternated rice paddies, and double cropping rice paddies, was evaluated, based on the datasets of soil organic matter content; and the total CH4 emission from rice paddies without straw return was estimated, with reference to the experimental data of paddies' CH4 emission and by the method of mean emission coefficient. The total CH4 emission from our paddies after straw return and the global warming potential of the increased CH4 emission were also estimated by using the related methods and parameters given by IPCC. It was estimated that the full popularization of straw return to China's rice paddies would sequester 10.48 Tg x a(-1) of C, and the contribution to the global warming mitigation was 38.43 Tg CO2-eqv x a(-1). In the meanwhile, the CH4 emission from our rice paddies would be increased from 5.796 Tg x a(-1) to 9.114 Tg x a(-1), and the increased 3.318 Tg x a(-1) of CH4 emission would lead to a global warming potential of 82.95 Tg CO2 -eqv x a(-1), which was 2.158 times of the mitigation from carbon sequestration in rice paddies. Therefore, the increased CH4 emission due to straw return should be regarded as an important greenhouse gas leakage, since it could greatly offset the mitigation benefits of soil carbon sequestration in China's rice paddies.


Impact of bacterial infection and intestinal microbiome on colorectal cancer development.
Accumulating evidence suggests that intestinal bacteria play an important role in the pathogenesis of colorectal cancer (CRC). Due to the complexity of the intestinal microbiome, identification of the specific causative microbial agents in CRC remains challenging, and the search for the causative microbial agents is intense. However, whether bacteria or their products can induce inflammation that results in tumorigenesis or directly causes CRC in humans is still not clear. This review will mainly focus on the progress of bacterial infection and CRC, and introduce the microbial contribution to the hallmarks of cancer. This article uses Salmonella and its chronic infection as an example to investigate a single pathogen and its role in the development of CRC, based on laboratory and epidemiological evidence. The bacterial infection leads to an altered intestinal microbiome. The review also discusses the dysfunction of the microbiome and the mechanism of host-microbial interactions, for example, bacterial virulence factors, key signaling pathways in the host, and microbial post-translational modifications in the tumorigenesis. Colonic carcinogenesis involves a progressive accumulation of mutations in a genetically susceptible host leading to cellular autonomy. Moving forward, more human data are needed to confirm the direct roles of bacterial infection in CRC development. Insights into the inhibiting infection will help to prevent cancer and develop strategies to restore the balance between host and microorganisms.


Management of spinal cord compression caused by extramedullary hematopoiesis in beta-thalassemia.
Thalassemia is a chronic hemolytic anemia, endemic around the Mediterranean basin. Extramedullary hematopoiesis (EMH) is a normal compensatory reaction that can involve many organs or tissues, including the epidural space, leading to a spinal cord compression syndrome. In almost all cases, the clinical and MR patterns are those of a lower dorsal spinal cord progressive compression secondary to an epidural expanding process. The management still remains controversial, including mainly blood transfusions, decompressive surgery and radiotherapy. We present a case of EMH in a thalassemic adolescent boy presenting with a T12 level of compression, treated successfully with blood transfusion, surgical decompression and radiotherapy.


Microbiological selenate to selenite conversion for selenium removal.
Removal of the toxic selenium compounds selenite and selenate from waste water before discharge is becoming increasingly imperative in industrialized countries. Bacteria can reduce selenate to selenite, but also further to elemental selenium, selenide or organic selenium. In this paper, we aim to exclusively bio-reduce selenate to selenite in an open high-rate bioreactor. This conversion could be part of a two-stage process in which the selenite is subsequently reduced by chemical means under optimal conditions to produce a biomass-free selenium product. In the process, yield and reduction rate of biological selenate to selenite should be maximized, while formation of elemental selenium, selenide and organic selenium compounds should be avoided. Fed-batch experiments with a liquid volume of 0.25-0.75 L at different temperatures 20-30-40-50 °C, pH settings 6-7-8-9, initial biomass concentration of 1 or 5 g wet weight granular Eerbeek sludge and various lactic acid concentrations were performed to determine their effect on the biological conversion of selenate to selenite. Furthermore, the effect on selenite losses by further biological reduction or, if present, chemical reduction was investigated as well. Optimal selenate reduction to selenite was found at 30 °C and pH 6 or 7 or 8 with 25 mM selenate and 13.75 mM lactic acid in the influent, with a selenite yield of 79-95%. In all the other conditions, less selenate was reduced to selenite. Also a 5 times higher electron donor concentration resulted in less selenite production, with only 22% of the selenate converted to selenite. The high yield and the high biological reduction rate of at least 741 mg Se/g initial VSS/day detected in the 1 g initial biomass experiment implicate that biological selenate conversion to selenite is a feasible process.


Research recommendations for selected IARC-classified agents.
There are some common occupational agents and exposure circumstances for which evidence of carcinogenicity is substantial but not yet conclusive for humans. Our objectives were to identify research gaps and needs for 20 agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. For each chemical agent (or category of agents), a systematic review was conducted of new data published since the most recent pertinent International Agency for Research on Cancer (IARC) Monograph meeting on that agent. Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress, and immuno- and hormonal modulation. Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.


Prevalence of Inadequate Cervical Cancer Screening in Low-Income Older Women.
Objective: At age 65 years, cervical cancer screening is not recommended in women with an adequate history of negative screening tests in the previous 10 years if they do not have other high-risk factors for cervical cancer. The purpose of this study was to assess the proportion of older low-income women at a safety net urban hospital system without other risk factors for cervical cancer who should have cervical cancer screening because of an inadequate screening history, and to evaluate if they were triaged appropriately. Materials and Methods: Medical records from 200 women 65 years and older at the Gynecology clinic of John H. Stroger Hospital of Cook County were evaluated for adequate cervical cancer screening or hysterectomy to see if they could stop screening. Charts were reviewed to see if a screen was performed, and the results of that test and associated biopsies. Data using cytology alone and the cytology/human papillomavirus cotest were compared. Chi-square test was used. Results: Of 200 women included, the median age was 68.5 years, range 65-93 years. Of these women, 81 (40.5%) did not need testing because of adequate screening or hysterectomy for benign indications. There were 119 (59.5%) women who needed to continue testing because of inadequate screening. Of these women, 46 (38.7%) did not have appropriate testing carried out. Of 73 correctly screened women, 16 (21.9%) required biopsies, of which 11 demonstrated high-grade lesions or cancers. Conclusions: Many older women, especially low-income women, need to continue screening for cervical cancer because of inadequate screening histories. This is a group at increased risk for cervical cancer, and it is imperative that clinicians evaluate previous test results before exiting a woman from screening at age 65 years.


RAD50/MRE11/NBS1 proteins in relation to tumour development and prognosis in patients with microsatellite stable colorectal cancer.
RAD50/MRE11/NBS1 complex is essential for DNA double-strand break repair and for maintaining genomic integrity. In this study, we immunohistochemically examined MRE11, NBS1 and RAD50 expression in primary CRCs (n=208), the corresponding distant (n=41) and adjacent normal mucosa (n=130), and lymph node metastases (n=26), and investigated their clinicopathological significance in colorectal cancers (CRCs). We found that the intensity and percentage of MRE11 and NBS1 in primary CRCs were positively correlated with each other and with RAD50 (P<0.0001). Strong expression of MRE11, NBS1 or combined RAD50/MRE11/NBS1 was related to MSS, positive hMLH1 expression, earlier tumour stage (TNM stage I and II) and favourable survival (P<0.05). A high percentage of MRE11 expression was associated with less local recurrence and high apoptotic activity (P<0.05). In MSS CRCs, the expression of MRE11 and NBS1 was stronger than that in normal mucosa (P<0.05), and strong expression of NBS1 in primary tumour was related to favourable survival of patients in TNM stage I and II (univariate analysis: P=0.03; multivariate analysis: P=0.07). In MSI CRCs, neither MRE11 nor NBS1 expression showed differences among normal mucosa, primary tumour and metastasis, or among clinicopathological variables. In conclusion, RAD50/MRE11/NBS1 proteins interacted with each other, which had different clinicopathological significance in MSS and MSI CRCs, and further, each component of the complex might have additional roles. NBS1 might be a prognostic factor for patients with MSS tumour in TNM stage I and II.


Racial differences in the progression from chronic renal insufficiency to end-stage renal disease in the United States.
Black Americans experience a disproportionate burden of ESRD compared with whites. Whether this is caused by the increased prevalence of chronic renal insufficiency (CRI) among blacks or by their increased progression from CRI to ESRD was investigated. A birth cohort analysis was performed using data from the Third National Health and Nutrition Examination Survey and the United States Renal Data System. It was assumed that those who developed ESRD in 1996 aged 25 to 79 yr came from the source population with CRI aged 20 to 74 yr that was sampled in the Third National Health and Nutrition Examination Survey (midpoint 1991). GFR was estimated using the Modification of Diet in Renal Disease study equation. The prevalence of CRI (GFR 15 to 59 ml/min per 1.73 m(2)) was not different among black compared with white adults (2060 versus 2520 per 100,000; P = 0.14). For each 100 blacks with CRI in 1991, five new cases of ESRD developed in 1996, whereas only one case of ESRD developed per 100 whites with CRI (risk ratio, 4.8; 95% confidence interval, 2.9 to 8.4). The increased risk for blacks compared with whites was only modestly affected by adjustment for age, gender, and diabetes. Blacks with CRI had higher systolic (147 versus 136 mmHg; P = 0.001) and diastolic (82 versus 77 mmHg; P = 0.02) BP and greater albuminuria (422 versus 158 micro g urine albumin/mg urine creatinine; P = 0.01). The higher incidence of ESRD among blacks is not due to a greater prevalence of CRI among blacks. The key to understanding black-white differences in ESRD incidence lies in understanding the extreme differences in their progression from CRI to ESRD.


Improvement in nitrogen fixation capacity could be part of the domestication process in soybean.
Biological nitrogen fixation (BNF) in soybeans is a complex process involving the interplay between the plant host and the symbiotic rhizobia. As nitrogen supply has a crucial role in growth and development, higher nitrogen fixation capacity would be important to achieve bigger plants and larger seeds, which were important selection criteria during plant domestication by humans. To test this hypothesis, we monitored the nitrogen fixation-related performance in 31 cultivated and 17 wild soybeans after inoculation with the slow-growing Bradyrhizobium diazoefficiens sp. nov. USDA110 and the fast-growing Sinorhizobium (Ensifer) fredii CCBAU45436. Our results showed that, in general, cultivated soybeans gave better performance in BNF. Electron microscopic studies indicated that there was an exceptionally high accumulation of poly-β-hydroxybutyrate bodies in bacteroids in the nodules of all wild soybeans tested, suggesting that the C/N balance in wild soybeans may not be optimized for nitrogen fixation. Furthermore, we identified new quantitative trait loci (QTLs) for total ureides and total nodule fresh weight by employing a recombinant inbred population composed of descendants from a cross between a cultivated and a wild parent. Using nucleotide diversity (θπ), divergence index (Fst) and distribution of fixed single-nucleotide polymorphisms as parameters, we found that some regions in the total ureides QTL on chromosome 17 and the total nodule fresh weight QTL on chromosome 12 exhibited very low diversity among cultivated soybeans, suggesting that these were traits specially selected during the domestication and breeding process.


Resonant and non-resonant magnetic scatterings with circularly polarized X-rays: magnetic scattering factor and electron density of gadolinium iron garnet.
Theoretical and experimental studies on resonant magnetic scattering have been carried out using circularly polarized X-rays. Polarization dependence of the asymmetric ratio between right- and left-handed polarized scattering amplitudes has revealed that resonant and non-resonant magnetic scatterings can be observed simultaneously. In this study, synchrotron X-ray intensity experiments were conducted on Gd iron garnet (GdIG) at the pre-edge of the Fe K absorption edge. The asymmetric ratio between circular polarizations exhibited three peaks due to the resonant magnetic responses of Fe3+ in the Fe2 (24d) site. These magnetic responses are antiparallel and have apparently higher resolution than dispersive X-ray magnetic circular dichroism at the pre-edge region; this can be mainly attributed to electric dipole transitions from 1s to t2 energy levels of the 3d orbitals in the tetrahedral symmetry in an unstable state quenched at higher temperature. Resonant magnetic scattering factors f'm were estimated from the asymmetric ratios. Fourier analysis was conducted using the intensity differences among circularly polarized X-rays at an energy of E = 7.1085 keV. At this energy level, the characteristic distribution of magnetic electron density was clearly observed. This distribution was interpreted as a spin arrangement of Gd and Fe ions in GdIG. Also observed was the presence of hybridization of the magnetic electron orbitals as well as of the resonant magnetic Fe3+. The proposed method has the potential to be widely used in crystal structure analysis.


Artificial intelligence in retinal imaging: current status and future prospects.
The steadily growing and aging world population, in conjunction with continuously increasing prevalences of vision-threatening retinal diseases, is placing an increasing burden on the global healthcare system. The main challenges within retinology involve identifying the comparatively few patients requiring therapy within the large mass, the assurance of comprehensive screening for retinal disease and individualized therapy planning. In order to sustain high-quality ophthalmic care in the future, the incorporation of artificial intelligence (AI) technologies into our clinical practice represents a potential solution. This review sheds light onto already realized and promising future applications of AI techniques in retinal imaging. The main attention is directed at the application in diabetic retinopathy and age-related macular degeneration. The principles of use in disease screening, grading, therapeutic planning and prediction of future developments are explained based on the currently available literature. The recent accomplishments of AI in retinal imaging indicate that its implementation into our daily practice is likely to fundamentally change the ophthalmic healthcare system and bring us one step closer to the goal of individualized treatment. However, it must be emphasized that the aim is to optimally support clinicians by gradually incorporating AI approaches, rather than replacing ophthalmologists.


Influence of socioeconomic level and dentifrice brand on the oral hygiene habits and the fluoride dentifrice ingestion.
The aim of this study was to evaluate the influence of socioeconomic level and dentifrice brand on the brushing habits and the fluoride ingestion. The sample was composed of 124 Brazilian children aged 3-9 years, from different socioeconomic levels (SEL). It was used a crossover study with the children using two dentifrice brands: Tandy Uva/T (1,100 ppm NaF) and Super Branco/SB (1,500 ppm MFP). Each child brushed his/her teeth with both dentifrice brands with weekly intervals between the brushes. The oral hygiene habits considered in this study were the Dentifrice Amount Placed on toothbrush (ADP), Dentifrice Amount Ingested (ADI), Fluoride Amount Ingested (FAI) and Brushing Time (TB). The data obtained were submitted to ANOVA test. It was observed that there was influence of SEL on the ADP and TB. The high SEL children showed a higher ADP and TB. The dentifrice brand influenced significantly the ADP, ADI, AFI and TB; the dentifrice T showed a higher ADP, ADI, but a lower AFI and TB. The results showed a significant interaction between SEL and dentifrice brand as ADI, AFI and TB. Although the children ingested a higher amount of T dentifrice they ingested a higher amount of fluoride from the SB dentifrice.


Sensitivity of cAMP-stimulated salt secretion in shark rectal gland to "loop" diuretics.
The secretory response of isolated perfused shark rectal gland was characterized with respect to its inhibition by a chemically related series of 5-sulfamoylbenzoic acid derivatives and certain phenoxyacetic acid derivatives. Maximal fluid and salt secretion was elicited with dibutyryl adenosine 3',5'-cyclic monophosphate and theophylline. The potency series established for the 5-sulfamoylbenzoic acid compounds agreed well with the relative potencies previously established for these agents as inhibitors of Na+-K+-Cl- cotransport in the avian erythrocyte. The most potent compound tested (3-benzylamino-4-phenyl-5-sulfamoylbenzoic acid) had a 50% inhibitory concentration value of approximately 5 X 10(-7) M. This compound was approximately 10-fold more effective than bumetanide and 400-fold as inhibitory as furosemide in this system. Ethacrynic acid (EA; 10(-3) M) was a poor inhibitor of rectal gland secretion and was approximately equipotent with its saturated derivative, dihydro EA. In contrast, EA-L-cysteine was fully effective at 10(-4) M, although the EA-D-cysteine adduct was ineffective. These data also qualitatively agree with results obtained in the inhibition of avian erythrocyte Na+-K+-Cl- cotransport and suggest that the rectal gland possesses a serosally oriented "NaCl cotransport" system with pharmacological and perhaps physiological similarities to the Na+-K+-Cl-cotransporter found in erythrocyte and other cell membranes.


Evaluation and management of plaque protrusion or thrombus following carotid artery stenting.
Carotid artery stenting (CAS) has become a common treatment for carotid artery stenosis. However, complications, such as an ischemic event, can occur with CAS during intra- and post-operative periods. Among these ischemic complications, plaque protrusion into the stent and thrombus on the stent have occurred after CAS. We retrospectively evaluated the temporal profile and treatment options for these complications in 32 consecutive cases who underwent CAS at our hospital between April 2009 and December 2011. The cases were evaluated pre-operatively for risk factors, as well as the plaque morphology and characteristics using computed tomographic angiography (CTA), ultrasound (US), and magnetic resonance imaging (MRI). Post-operatively, lesions were examined by CTA and/or US within 1 week of CAS. As a result, among the 32 cases, 8 experienced plaque protrusions or thrombus, which were treated with medication (anti-platelet and/or anti-coagulation reinforcement). In 7 of these 8 cases, the plaque protrusion or thrombus was stabilized with medication alone. However, the remaining case showed growth and migration of the plaque protrusion or thrombus when treated with medication alone, and therefore, required further endovascular treatment. We identified that a history of symptomatic cerebral infarction and plaques with ulceration were risk factors for plaque protrusion or thrombus formation after CAS, and pre dilatation can decrease the risk of these complications. Medication was effective in most cases of plaque protrusion or thrombus; however, further endovascular treatment was required when medication alone was unsuccessful.


Functional brain organization of preparatory attentional control in visual search.
Looking for an object that may be present in a cluttered visual display requires an advanced specification of that object to be created and then matched against the incoming visual input. Here, fast event-related fMRI was used to identify the brain networks that are active when preparing to search for a visual target. By isolating the preparation phase of the task it has been possible to show that for an identical stimulus, different patterns of cortical activation occur depending on whether participants anticipate a 'feature' or a 'conjunction' search task. When anticipating a conjunction search task, there was more robust activation in ventral occipital areas, new activity in the transverse occipital sulci and right posterior intraparietal sulcus. In addition, preparing for either type of search activated ventral striatum and lateral cerebellum. These results suggest that when participants anticipate a demanding search task, they develop a different advanced representation of a visually identical target stimulus compared to when they anticipate a nondemanding search.


Medial temporal lobe contributions to episodic sequence encoding.
Memory for the order of events within an episode requires mechanisms capable of bridging gaps between those events and laying down memory traces that will support the subsequent retrieval of episodic sequence information. It has been proposed that the hippocampus and surrounding medial temporal lobe (MTL) play a critical role in these processes. Here, using functional magnetic resonance imaging, we examined MTL activation during the encoding of sequentially presented noun triplets. Using performance on a retrieval test, encoding activations predictive of subsequent triplet recognition ("hits" vs. "misses") as well as activations differentiating triplets that were subsequently recognized with (ordered) and without (misordered) memory for the original sequence of presentation were identified. Within the MTL, activations in bilateral hippocampal and parahippocampal cortical regions predicted subsequent order memory, with greater activations observed during encoding of triplets subsequently correctly ordered than those subsequently misordered. Interestingly, activation in these regions did not correlate with old/new triplet identification, suggesting that these MTL regions contributed specifically to encoding of episodic details supporting subsequent recovery of sequence information.


Variation in photosynthetic traits related to access to water in semiarid Australian woody species.
Low soil water content can limit photosynthesis by reducing stomatal conductance. Here, we explore relationships among traits pertaining to carbon uptake and pre-dawn leaf water potential (as an index of soil water availability) across eight species found in semiarid central Australia. We found that as pre-dawn leaf water potential declined, stomatal limitations to photosynthesis increased, as did foliar nitrogen, which enhanced photosynthesis. Nitrogen-fixing Acacia species had higher foliar nitrogen concentrations compared with non-nitrogen fixing species, although there was considerable variability of traits within the Acacia genus. From principal component analysis we found that the most dissimilar species was Acacia aptaneura Maslin&J.E.Reid compared with both Eucalyptus camaldulensis Dehnh. and Corymbia opaca. (D.J.Carr & S.G.M.Carr)K.D.Hill&L.A.S.Johnson, having both the largest foliar N content, equal largest leaf mass per area and experiencing the lowest pre-dawn water potential of all species. A. aptaneura has shallow roots and grows above a hardpan that excludes access to groundwater, in contrast to E. camaldulensis and C. opaca, which are known to access groundwater. We conclude that ecohydrological niche separation is an important factor driving the variability of within-biome traits related to carbon gain. These observations have important implications for global vegetation models, which are parameterised with many of the traits measured here, but are often limited by data availability.


The prognostic value of CT coronary angiography in patients attending hospital with troponin-negative acute chest pain and inconclusive exercise treadmill tests.
Once acute coronary syndrome (ACS) is excluded in patients presenting to hospital with acute chest pain, usual practice is to stratify future risk of adverse cardiovascular events. Commonly this is performed by pre-discharge exercise treadmill testing (ETT). Often however, patients are unable to perform the test for various reasons, or the final result is inconclusive. This potentially could lead to uncertainty and to unnecessary invasive coronary angiography. We wished to evaluate the potential prognostic significance of CT coronary angiography (CTCA) in patients with prior inconclusive ETTs. Two hundred and thirty-two consecutive patients underwent CTCA and calcium scoring following hospital attendance with acute chest pain and following exclusion of ACS. All patients were followed up for a combined primary outcome of death, non-fatal myocardial infarction, and late revascularization. The mean follow-up period was 2.5 ± 0.9 years. The combined primary outcome occurred in 26 patients (11.2%). Calcium score (HR 1.16; 95% CI 1.02-1.31, P = 0.023 per 100 Agatston unit increase), the presence of coronary artery disease (CAD) on CTCA (non-obstructive CAD, HR 4.52; 95% CI 1.30-15.73, P = 0.018; obstructive CAD, HR 17.00; 95% CI 4.60-62.85, P < 0.001), and ≥3 segments with non-calcified plaque (HR 3.30; 95% CI 1.24-8.76, P = 0.017) were significant univariable predictors of the primary outcome. CTCA was the only significant multivariable predictor of adverse outcome. The presence of CAD assessed by CTCA is a strong predictor of adverse events in patients with troponin-negative acute chest pain and could potentially be used as an alternative, non-invasive risk stratifier in patients with inconclusive exercise tests.


Synergistic activity of piperacillin in combination with beta-lactamase inhibitors.
Clavulanic acid and a penicillanic acid sulfone, when combined individually with piperacillin, synergistically inhibited various Enterobacteriaceae, Staphylococcus aureus, and Bacteroides fragilis. Clavulanic acid and piperacillin synergistically inhibited 91 of 170 (55%) isolates tested. Synergy was most often found against piperacillin-resistant bacteria: 65 of 69 isolates (94%). Although the penicillanic acid sulfone acted synergistically with piperacillin, inhibiting 62 of 170 strains (33%), the concentration of clavulanic acid required for synergy generally was less than that of penicillanic acid sulfone. Combination of piperacillin and cefotaxime, an inhibitor of type 1 beta-lactamases, rarely was synergistic and was antagonistic for several species. The combination of piperacillin with potent beta-lactamase inhibitors made piperacillin active against those isolates of Escherichia coli and Klebsiella and Bacteroides species, as well as selected other species, that are resistant to piperacillin by virtue of their production of beta-lactamases.


Comparison of clinical features between non-smokers with COPD and smokers with COPD: a retrospective observational study.
Smoking is a major risk factor for chronic obstructive pulmonary disease (COPD); however, the similarities and differences in clinical presentation between smokers and nonsmokers are not fully described in patients with COPD. This study was designed to address this issue in a general teaching hospital in the People's Republic of China. The medical records of patients hospitalized with a lung mass for further evaluation at Zhongshan Hospital, Fudan University, from January 2006 to December 2010 were reviewed and the data of interest were collected. The definition of COPD was according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric criteria. Participants who had a previous exacerbation within 4 weeks of admission, airflow limitation due to abnormalities in the large airways, or with other pulmonary diseases were excluded. Included subjects were divided into nonsmokers with COPD and smokers with COPD by a cutoff of a 5 pack-year smoking history. A total of 605 subjects were included in the final analysis. The average age was 64.8±8.5 years and 62.0% (375/605) were smokers. Eighty percent of the patients had mild to moderate disease (GOLD grade 1-2). Age and years with COPD were comparable between the two groups. Compared with smokers with COPD, nonsmokers with COPD were more likely to be female, reported less chronic cough and sputum, have less emphysema on radiologic examination, and higher measures of forced expiratory volume in the first second percent predicted (FEV1), forced expiratory volume in one second/forced vital capacity (FEV1/FVC%) percent predicted, maximal voluntary ventilation percent predicted, diffusing capacity of lung (DLCO) percent predicted, and DLCO/alveolar volume percent predicted, with lower levels of residual volume percent predicted and residual volume/total lung capacity percent predicted. There were no significant differences between the two groups with regard to distribution of disease severity, vital capacity percent predicted, total lung capacity percent predicted, PaO2, PaCO2, modified Medical Research Council dyspnea score, wheezing, airway reversibility, and comorbidities. Smoking amount (pack-years) was correlated negatively with FEV1 percent predicted, FEV1/FVC% percent predicted, inspiratory capacity percent predicted, inspiratory capacity/total lung capacity percent predicted, and DLCO percent predicted, and correlated positively with GOLD grade and symptoms. Non-smokers with COPD had less impairment in airflow limitation and gas exchange, and a lower prevalence of emphysema, chronic cough, and sputum compared with their smoking counterparts. Tobacco cessation is warranted in smokers with COPD.


Venous thromboembolism risk assessment in hospitalised patients: a new proposal.
Cross-sectional studies have been conducted to evaluate the adequacy of prophylaxis for venous thromboembolism. However, these studies often evaluate prophylaxis on the data collection day, without analysing the prophylactic dose or duration and without reference to inappropriate use in patients without risk. A prospective, observational study was performed to assess the adequacy of prophylaxis in a general medicine ward of a university hospital. In the analysis, the use of the proper prophylactic dose at the correct time, the use in patients with contraindications, and the misuse in patients without risk of venous thromboembolism were considered. A total of 245 patients were evaluated. Of these patients, 104 (42.4%) were considered to be at risk, and 82.7% either received adequate prophylaxis (i.e., the correct dose at the right time) or did not receive prophylaxis because it was contraindicated. Among the 141 patients who were not at risk, 81 (57.4%) incorrectly received prophylaxis, the majority (61/81) of whom presented with risk factors but did not demonstrate reduced mobility. Among the entire group, only 59.6% of patients were properly treated. The evaluation of prophylaxis adequacy should consider not only whether the correct dose is administered at the correct time but also whether it is used in patients with contraindications and whether it is inappropriately administered to patients who are not at risk.


Infants' haptic perception of object unity in rotating displays.
Four-month-old infants were allowed to manipulate, without vision, two rings attached to a bar that permitted each ring to undergo rotary motion against a fixed surface. In different conditions, the relative motions of the rings were rigid, independent, or opposite, and they circled either the same fixed point outside the zone of manipulation or spatially separated points. Infants' perception of the ring assemblies were affected by the nature of the rotary motion in two ways. First, infants perceived a unitary object when the felt ends of the object underwent a common, rigid rotary motion; perception of object unity was stronger in this condition than when the ends underwent either independent or opposite rotary motions. Second, infants perceived two distinct objects when the felt ends of the objects underwent independent rotary motions that centred on distinct fixed points. Perception of the distinctness of the objects was less clear when the ends underwent opposite or independent rotary motions that centred on a common fixed point. These findings provide the first evidence that infants are sensitive to rotary motion patterns and can extrapolate a global pattern of rigid motion from the distinct, local velocities that they produce and experience at their two hands.


The Developmental Trajectory of Self-Injurious Behaviours in Individuals with Prader Willi Syndrome, Autism Spectrum Disorder and Intellectual Disability.
In the present study we examined the nature and developmental trajectory of self-injurious behaviour in Prader Willi syndrome (PWS) and autism spectrum disorder (ASD). The development of interventions is greatly aided by understanding gene to behaviour pathways, and this requires an accurate description of the behaviour phenotype, that is, which types and natural history of self-injurious behaviour are more common in PWS and ASD and which are shared with other forms of developmental disability. Self-injury displayed by individuals with PWS and individuals with ASD was compared with that reported in a group of individuals with intellectual disability due to mixed aetiology (ID group). Three self-injurious behaviours (head banging, skin-picking and hitting and/or biting self) were measured on five occasions over 18 years using the Developmental Behaviour Checklist (DBC) a well-validated caregiver report measure. Rates of skin picking were higher in individuals with PWS and hitting and/or biting self was higher in individuals with ASD compared to the ID group. Rates of head banging were similar across the three groups. Over time, skin-picking and head banging increased with age for individuals with ASD and hitting and/or biting self increased for the PWS group. In the PWS and mixed ID groups head banging decreased with age. These findings suggest that the typology and developmental trajectories of self-injurious behaviours differ between those with PWS and ASD.


Interactions of organic anions with the organic cation transporter in renal BBMV.
It is generally assumed that the organic cation transport system in the renal proximal tubule is specific for organic cations and the transport of organic cations is not affected by organic anions. However, there are also data in the literature demonstrating that probenecid, a classical inhibitor of organic anion transport systems, inhibits the transport of an organic cation, cimetidine, in the renal proximal tubule. In this study we investigated the effects of probenecid and furosemide on the transport of N'-methylnicotinamide (NMN) the classical substrate of the organic cation transporter, in brush-border membrane vesicles prepared from rabbit renal cortex. In the presence of a pH gradient, both probenecid (10 mM) and furosemide reduced the initial uptake of NMN. Probenecid reduced the initial uptake of NMN to 12.1% of the control values (1.19 +/- 0.26 pmol/mg) and furosemide reduced the initial uptake of NMN to 39.2%. Probenecid (10 mM) also decreased the initial transport of NMN in the absence of a pH gradient. Inhibition of the transport of NMN by probenecid was concentration dependent, with the concentration of probenecid resulting in 50% inhibition of the transport of NMN equal to 2.31 +/- 1.18 mM in the presence of a pH gradient. Probenecid appeared to be a competitive inhibitor of NMN transport. The apparent Km (mean +/- SE) of NMN transport (2.01 +/- 0.78 mM) was increased to 18.7 +/- 10 mM (P less than 0.05) by probenecid (10 mM), whereas the Vmax was not changed (125 +/- 19.2 pmol.s-1.mg-1 vs. 186 +/- 94 pmol.s-1.mg-1, P greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Protein kinase C in cancer: The top five unanswered questions.
Few kinases have been studied as extensively as protein kinase C (PKC), particularly in the context of cancer. As major cellular targets for the phorbol ester tumor promoters and diacylglycerol (DAG), a second messenger generated by stimulation of membrane receptors, PKC isozymes play major roles in the control of signaling pathways associated with proliferation, migration, invasion, tumorigenesis, and metastasis. However, despite decades of research, fundamental questions remain to be answered or are the subject of intense controversy. Primary among these unresolved issues are the role of PKC isozymes as either tumor promoter or tumor suppressor kinases and the incomplete understanding on isozyme-specific substrates and effectors. The involvement of PKC isozymes in cancer progression needs to be reassessed in the context of specific oncogenic and tumor suppressing alterations. In addition, there are still major hurdles in addressing isozyme-specific function due to the limited specificity of most pharmacological PKC modulators and the lack of validated predictive biomarkers for response, which impacts the translation of these agents to the clinic. In this review we focus on key controversial issues and upcoming challenges, with the expectation that understanding the intricacies of PKC function will help fulfill the yet unsuccessful promise of targeting PKCs for cancer therapeutics.


Rheology and stability of acidified food emulsions treated with high pressure.
The stability and rheology of acidified model oil-in-water emulsions (pH 3.6 +/- 0.1) were evaluated before and after high-pressure treatments. Varying concentrations of canola oil (0-50% w/w), whey protein isolate, polysorbate 60, soy lecithin (0.1-1.5% w/w each), and xanthan (0.0-0.2% w/w) were chosen. Exposure to high pressures (up to 800 MPa for 5 min at 30 degrees C) did not significantly affect the equivalent surface mean diameter D[3,2], flow behavior, and viscoelasticity of the whey protein isolate and polysorbate 60-stabilized emulsions. Pressure treatments had negligible effects on emulsion stability in these systems, except when xanthan (0.2% w/w) was present in which pressure improved the stability of polysorbate 60-stabilized emulsions. Soy lecithin-stabilized emulsions had larger mean particles sizes and lower emulsion volume indices than the others, indicating potential instability, and application of pressure further destabilized these emulsions.


A method to study cell proliferation kinetics in human gastric mucosa.
The purpose of this investigation was to study cell proliferation kinetics in human gastric mucosa. Biopsies were taken from the antral and fundic part of the stomach through a fibre-gastroscope and incubated in culture medium containing a DNA-precursor (3-H-thymidine). Autoradiographs were prepared by the dipping technique. The number of labelled cells and the total number of cells in all cross sections of foveolae containing one or more labelled cells were counted. The labelling index (LI), which is defined as the percentage of labelled cells in the progenitor cell region, was estimated. When only cross sections with labelled cells are taken into consideration, the labelling index will be a little overestimated. In order to reduce this error a formula for correction was worked out. Thirty-six patients with different gastric diseases were studied. The observer error was minimal, and the results were highly reproducible. It was not possible to demonstrate any correlation between the labelling indices in antral and fundic mucosa. A significantly increased epithelial proliferation was found in fundic mucosa from patients with gastric cancer and atrophic gastritis.


Criticality in the slowed-down boiling crisis at zero gravity.
Boiling crisis is a transition between nucleate and film boiling. It occurs at a threshold value of the heat flux from the heater called CHF (critical heat flux). Usually, boiling crisis studies are hindered by the high CHF and short transition duration (below 1 ms). Here we report on experiments in hydrogen near its liquid-vapor critical point, in which the CHF is low and the dynamics slow enough to be resolved. As under such conditions the surface tension is very small, the experiments are carried out in the reduced gravity to preserve the conventional bubble geometry. Weightlessness is created artificially in two-phase hydrogen by compensating gravity with magnetic forces. We were able to reveal the fractal structure of the contour of the percolating cluster of the dry areas at the heater that precedes the boiling crisis. We provide a direct statistical analysis of dry spot areas that confirms the boiling crisis at zero gravity as a scale-free phenomenon. It was observed that, in agreement with theoretical predictions, saturated boiling CHF tends to zero (within the precision of our thermal control system) in zero gravity, which suggests that the boiling crisis may be observed at any heat flux provided the experiment lasts long enough.


Effects of scatter substraction on detection and quantitation in hepatic SPECT.
The purpose of this investigation was to examine the effects of subtractive scatter compensation methods on lesion detection and quantitation. Receiver operating characteristic (ROC) methodology was used to measure human observer detection accuracy for tumors in the liver using synthetic images. Furthermore, ROC results were compared with mathematical models for detection and activity quantitation to examine (a) the potential for predicting human performance and (b) the relationship between the detection and quantitation tasks. Images with both low and high amounts of scatter were compared with the ideal case of images of primary photons only (i.e., perfect scatter rejection) and with images corrected by subtracting a scatter image estimated by the dual photopeak window method. With low contrast tumors in a low count background, the results showed that scatter subtraction improved quantitation but did not produce statistically significant increases in detection accuracy. However, primary images did produce some statistically significant improvements in detection accuracy when compared with uncorrected images, particularly for high levels of scatter. Although scatter subtraction methods may provide improved activity quantitation, they may not significantly improve detection for liver SPECT. The results imply that significant improvement in detection accuracy for the conditions tested may depend on the development of gamma cameras with better scatter rejection.


The pathogenesis of cardiomyopathy in Friedreich ataxia.
Friedreich ataxia (FA) is an autosomal recessive disease with a complex neurological phenotype, but the most common cause of death is heart failure. This study presents a systematic analysis of 15 fixed and 13 frozen archival autopsy tissues of FA hearts and 10 normal controls (8 frozen) by measurement of cardiomyocyte hypertrophy; tissue frataxin assay; X-ray fluorescence (XRF) of iron (Fe) and zinc (Zn) in polyethylene glycol-embedded samples of left and right ventricular walls (LVW, RVW) and ventricular septum (VS); metal quantification in bulk digests by inductively-coupled plasma optical emission spectrometry (ICP-OES); Fe histochemistry; and immunohistochemistry and immunofluorescence of cytosolic and mitochondrial ferritins and of the inflammatory markers CD68 and hepcidin. FA cardiomyocytes were significantly larger than normal and surrounded by fibrotic endomysium. Frataxin in LVW was reduced to less than 15 ng/g wet weight (normal 235.4 ± 75.1 ng/g). All sections displayed characteristic Fe-reactive inclusions in cardiomyocytes, and XRF confirmed significant regional Fe accumulation in LVW and VS. In contrast, ICP-OES analysis of bulk extracts revealed normal total Fe levels in LVW, RVW, and VS. Cardiac Zn remained normal by XRF and assay of bulk digests. Cytosolic and mitochondrial ferritins exhibited extensive co-localization in cardiomyocytes, representing translational and transcriptional responses to Fe, respectively. Fe accumulation progressed from a few small granules to coarse aggregates in phagocytized cardiomyocytes. All cases met the "Dallas criteria" of myocarditis. Inflammatory cells contained CD68 and cytosolic ferritin, and most also expressed the Fe-regulatory hormone hepcidin. Inflammation is an important factor in the pathogenesis of FA cardiomyopathy but may be more evident in advanced stages of the disease. Hepcidin-induced failure of Fe export from macrophages is a likely contributory cause of damage to the heart in FA. Frataxin replacement and anti-inflammatory agents are potential therapies in FA cardiomyopathy.


The superior olivary nucleus and its influence on nucleus laminaris: a source of inhibitory feedback for coincidence detection in the avian auditory brainstem.
Located in the ventrolateral region of the avian brainstem, the superior olivary nucleus (SON) receives inputs from nucleus angularis (NA) and nucleus laminaris (NL) and projects back to NA, NL, and nucleus magnocellularis (NM). The reciprocal connections between the SON and NL are of particular interest because they constitute a feedback circuit for coincidence detection. In the present study, the chick SON was investigated. In vivo tracing studies show that the SON projects predominantly to the ipsilateral NM, NL, and NA. In vitro whole-cell recording reveals single-cell morphology, firing properties, and postsynaptic responses. SON neurons are morphologically and physiologically suited for temporal integration; their firing patterns do not reflect the temporal structure of their excitatory inputs. Of most interest, direct stimulation of the SON evokes long-lasting inhibition in NL neurons. The inhibition blocks both intrinsic spike generation and orthodromically evoked activity in NL neurons and can be eliminated by bicuculline methiodide, a potent antagonist for GABAA receptor-mediated neurotransmission. These results strongly suggest that the SON provides GABAergic inhibitory feedback to laminaris neurons. We discuss a mechanism whereby SON-evoked GABAergic inhibition can influence the coding of interaural time differences for sound localization in the avian auditory brainstem.


Dynamic Response of Pseudomonas putida S12 to Sudden Addition of Toluene and the Potential Role of the Solvent Tolerance Gene trgI.
Pseudomonas putida S12 is exceptionally tolerant to various organic solvents. To obtain further insight into this bacterium's primary defence mechanisms towards these potentially harmful substances, we studied its genome wide transcriptional response to sudden addition of toluene. Global gene expression profiles were monitored for 30 minutes after toluene addition. During toluene exposure, high oxygen-affinity cytochrome c oxidase is specifically expressed to provide for an adequate proton gradient supporting solvent efflux mechanisms. Concomitantly, the glyoxylate bypass route was up-regulated, to repair an apparent toluene stress-induced redox imbalance. A knock-out mutant of trgI, a recently identified toluene-repressed gene, was investigated in order to identify TrgI function. Remarkably, upon addition of toluene the number of differentially expressed genes initially was much lower in the trgI-mutant than in the wild-type strain. This suggested that after deletion of trgI cells were better prepared for sudden organic solvent stress. Before, as well as after, addition of toluene many genes of highly diverse functions were differentially expressed in trgI-mutant cells as compared to wild-type cells. This led to the hypothesis that TrgI may not only be involved in the modulation of solvent-elicited responses but in addition may affect basal expression levels of large groups of genes.


The use of the condensed single protein production system for isotope-labeled outer membrane proteins, OmpA and OmpX in E. coli.
Gram-negative bacteria consist of two independent membranes, the inner cytoplasmic membrane and the outer membrane. The outer membrane contains a number of β-barrel proteins such as OmpF, OmpC, OmpA, and OmpX. In this article, we explored to use the condensed Single Protein Production (cSPP) system for isotope labelling of OmpA and OmpX for NMR structural study, both of which are known to consist of eight β-strands forming a barrel in the outer membrane. Using a deletion strain lacking all major outer membrane proteins, both OmpA and OmpX were expressed well in a 20-fold cSPP system. We demonstrated that outer membrane fractions prepared from the cSPP system in M9 medium containing ¹⁵N-NH₄Cl can be directly used for NMR structural study of the outer mebrane proteins without any further purification to get excellent [¹H-¹⁵N]-TROSY spectra. This method would be quite valuable for the study of pure proteins in their native membrane environment without the need of purification and reconstitution.


Clinical Characterization of Copy Number Variants Associated With Neurodevelopmental Disorders in a Large-scale Multiancestry Biobank.
Past studies identified rare copy number variants (CNVs) as risk factors for neurodevelopmental disorders (NDDs), including autism spectrum disorder and schizophrenia. However, the clinical characterization of NDD CNVs is understudied in population cohorts unselected for neuropsychiatric disorders and in cohorts of diverse ancestry. To identify individuals harboring NDD CNVs in a multiancestry biobank and to query their enrichment for select neuropsychiatric disorders as well as association with multiple medical disorders. In a series of phenotypic enrichment and association analyses, NDD CNVs were clinically characterized among 24 877 participants in the BioMe biobank, an electronic health record-linked biobank derived from the Mount Sinai Health System, New York, New York. Participants were recruited into the biobank since September 2007 across diverse ancestry and medical and neuropsychiatric specialties. For the current analyses, electronic health record data were analyzed from May 2004 through May 2019. NDD CNVs were identified using a consensus of 2 CNV calling algorithms, based on whole-exome sequencing and genotype array data, followed by novel in-silico clinical assessments. Of 24 877 participants, 14 586 (58.7%) were female; self-reported ancestry categories included 5965 (24.0%) who were of African ancestry, 7892 (31.7%) who were of European ancestry, and 8536 (34.3%) who were of Hispanic ancestry; and the mean (SD) age was 50.5 (17.3) years. Among 24 877 individuals, the prevalence of 64 NDD CNVs was 2.5% (n = 627), with prevalence varying by locus, corroborating the presence of some relatively highly prevalent NDD CNVs (eg, 15q11.2 deletion/duplication). An aggregate set of NDD CNVs were enriched for congenital disorders (odds ratio, 2.0; 95% CI, 1.1-3.5; P = .01) and major depressive disorder (odds ratio, 1.5; 95% CI, 1.1-2.0; P = .01). In a meta-analysis of medical diagnoses (n = 195 hierarchically clustered diagnostic codes), NDD CNVs were significantly associated with several medical outcomes, including essential hypertension (z score = 3.6; P = 2.8 × 10-4), kidney failure (z score = 3.3; P = 1.1 × 10-3), and obstructive sleep apnea (z score = 3.4; P = 8.1 × 10-4) and, in another analysis, morbid obesity (z score = 3.8; P = 1.3 × 10-4). Further, NDD CNVs were associated with increased body mass index in a multiancestry analysis (β = 0.19; 95% CI, 0.10-0.31; P = .003). For 36 common serum tests, there was no association with NDD CNVs. Clinical features of individuals harboring NDD CNVs were elucidated in a large-scale, multiancestry biobank, identifying enrichments for congenital disorders and major depressive disorder as well as associations with several medical outcomes, including hypertension, kidney failure, and obesity and obesity-related phenotypes, specifically obstructive sleep apnea and increased body mass index. The association between NDD CNVs and obesity outcomes indicate further potential pleiotropy of NDD CNVs beyond neurodevelopmental outcomes previously reported. Future clinical genetic investigations may lead to insights of at-risk individuals and therapeutic strategies targeting specific genetic variants. The importance of diverse inclusion within biobanks and considering the effect of rare genetic variants in a multiancestry context is evident.


Protection of Skin Fibroblasts from Infrared-A-Induced Photo-Damage Using Ginsenoside Rg3(S)-Incorporated Soybean Lecithin Liposomes.
Protection of skin cells from chronic infrared-A (IRA) irradiation is crucial for anti-photoaging of the skin. In this study, we investigated the protective activity of Rg3(S) and Rg3(S)-incorporated anionic soybean lecithin liposomes (Rg3/Lipo) with a size of approximately 150 nm against IRA-induced photodamage in human fibroblasts. The formulated Rg3/Lipo showed increased solubility in aqueous solution up to a concentration of 200 μg/ml, compared to free Rg3(S). In addition, Rg3/Lipo exhibited superior colloidal stability in aqueous solutions and biocompatibility for normal human dermal fibroblasts (NHDFs). After repeated IRA irradiation on NHDFs, elevated levels of cellular and mitochondrial reactive oxygen species (ROS) were greatly reduced by Rg3(S) and Rg3/Lipo. In addition, cells treated with Rg3/Lipo exhibited noticeably reduced apoptotic signals following IRA irradiation compared to untreated cells. Thus, considering aqueous solubility and cellular responses, Rg3/Lipo could serve as a promising infrared protector for healthy aging of skin cells.


[Overeating and restrained eaters: an affective neuroscience perspective].
Some subjects may overeat when they experience anxiety even if they chronically restrict their food consumption. This contradictory behavior is a dysfunctional emotional regulation mechanism, which promotes the development of obesity and eating disorders. We review studies from a research program where alimentary restriction and overeating are conceived under the perspective of affective neuroscience. In this framework, restrained eaters (RE) are described as subjects that are emotionally vulnerable and have dysfunctional emotional modulation strategies. We discuss empiric evidence about the influence of motivational systems on alimentary behavior. Electrophysiological observations in RE reveal a self-referential processing of food stimulus as well as dysfunctional processing during the differentiation of emotional expressions. We stress the role of emotional education and the creation of psychometric instruments designed for early detection of restrained eaters.


Evaluation of Exudative Pleural Effusions: A Multicenter, Prospective, Observational Study.
The aim of this study is to determine the diagnostic performances of pleural procedures in undiagnosed exudative pleural effusions and to evaluate factors suggestive of benign or malignant pleural effusions in tertiary care centers. This was a multicenter prospective observational study conducted between January 1 and December 31, 2018. A total of 777 patients with undiagnosed exudative pleural effusion after the initial work-up were evaluated. The results of diagnostic procedures and the patients' diagnoses were prospectively recorded. Sensitivity, specificity, and accuracy estimates with 95% confidence intervals were used to examine the performance of pleural procedures to detect malignancy. The mean age ± SD of the 777 patients was 62.0 ± 16.0 years, and 68.3% of them were male. The most common cause was malignancy (38.3%). Lung cancer was the leading cause of malignant pleural effusions (20.2%). The diagnostic sensitivity and accuracy of cytology were 59.5% and 84.3%, respectively. The diagnostic sensitivity of image-guided pleural biopsy was 86.4%. The addition of image-guided pleural biopsy to cytology increased diagnostic sensitivity to more than 90%. Thoracoscopic biopsy provided the highest diagnostic sensitivity (94.3%). The highest diagnostic sensitivity of cytology was determined in metastatic pleural effusion from breast cancer (86.7%). The diagnostic performance increases considerably when cytology is combined with image-guided pleural biopsy in malignant pleural effusions. However, to avoid unnecessary interventions and complications, the development of criteria to distinguish patients with benign pleural effusions is as important as the identification of patients with malignant pleural effusions.


Redefining tissue specificity of genetic regulation of gene expression in the presence of allelic heterogeneity.
Uncovering the functional impact of genetic variation on gene expression is important in understanding tissue biology and the pathogenesis of complex traits. Despite large efforts to map expression quantitative trait loci (eQTLs) across many human tissues, our ability to translate those findings to understanding human disease has been incomplete, and the majority of disease loci are not explained by association with expression of a target gene. Cell-type specificity and the presence of multiple independent causal variants for many eQTLs are potential confounders contributing to the apparent discrepancy with disease loci. In this study, we investigate the tissue specificity of genetic effects on gene expression and the overlap with disease loci while considering the presence of multiple causal variants within and across tissues. We find evidence of pervasive tissue specificity of eQTLs, often masked by linkage disequilibrium that misleads traditional meta-analytic approaches. We propose CAFEH (colocalization and fine-mapping in the presence of allelic heterogeneity), a Bayesian method that integrates genetic association data across multiple traits, incorporating linkage disequilibrium to identify causal variants. CAFEH outperforms previous approaches in colocalization and fine-mapping. Using CAFEH, we show that genes with highly tissue-specific genetic effects are under greater selection, enriched in differentiation and developmental processes, and more likely to be involved in human disease. Last, we demonstrate that CAFEH can efficiently leverage the widespread allelic heterogeneity in genetic regulation of gene expression to prioritize the target tissue in genome-wide association complex trait loci, thereby improving our ability to interpret complex trait genetics.


Dual-layer wavelet SVM for predicting protein structural class via the general form of Chou's pseudo amino acid composition.
A prior knowledge of protein structural class can provide useful information about its overall structure. So, it is vitally important to develop a computational prediction method for fast and accurately determining the protein structural class. In this paper, a dual-layer wavelet support vector machine (WSVM) is presented via the general form of Chou's pseudo amino acid composition, which is featured by introducing wavelet as a kernel and making decisions by the fusion from three individual classifiers. As a demonstration, the rigorous jackknife cross-validation tests were performed on two benchmark datasets, including the more challenging 25PDB dataset. Our success rates were reliable, and it has not escaped from our notice that the present method has specific ability to predict the most difficult case of α+β class. The program developed can be acquired freely on request from the authors.


Coordinate loss of a microRNA and protein-coding gene cooperate in the pathogenesis of 5q- syndrome.
Large chromosomal deletions are among the most common molecular abnormalities in cancer, yet the identification of relevant genes has proven difficult. The 5q- syndrome, a subtype of myelodysplastic syndrome (MDS), is a chromosomal deletion syndrome characterized by anemia and thrombocytosis. Although we have previously shown that hemizygous loss of RPS14 recapitulates the failed erythroid differentiation seen in 5q- syndrome, it does not affect thrombocytosis. Here we show that a microRNA located in the common deletion region of 5q- syndrome, miR-145, affects megakaryocyte and erythroid differentiation. We find that miR-145 functions through repression of Fli-1, a megakaryocyte and erythroid regulatory transcription factor. Patients with del(5q) MDS have decreased expression of miR-145 and increased expression of Fli-1. Overexpression of miR-145 or inhibition of Fli-1 decreases the production of megakaryocytic cells relative to erythroid cells, whereas inhibition of miR-145 or overexpression of Fli-1 has a reciprocal effect. Moreover, combined loss of miR-145 and RPS14 cooperates to alter erythroid-megakaryocytic differentiation in a manner similar to the 5q- syndrome. Taken together, these findings demonstrate that coordinate deletion of a miRNA and a protein-coding gene contributes to the phenotype of a human malignancy, the 5q- syndrome.